By systematically integrating gene expression profiles and genomic imbalances of carcinomas using comparative genomic hybridization, we could show that DNA copy number gains of recurrently aneuploid chromosomes and chromosome arms 7, 8q, 13q, and 20q, and losses of 17p and 18q correlated significantly with the expression profiles of resident genes. Taken together, our results demonstrate that both, the high-level, significant transcriptional deregulation of specific genes and the average transcript levels of genes residing on aneuploid chromosomes coexist in colorectal adenocarcinomas (and other rumors of epithelial origin). In order to characterize patterns of global transcriptional deregulation in primary colon carcinomas, we performed gene expression profiling of some 300 tumors, including colon and rectum using oligonucleotide microarrays. For most of these tumors, expression profiles were compared to those from matched normal mucosa samples. We established a relationship between specific genomic imbalances, which were mapped for many of the analyzed colon tumors by comparative genomic hybridization, and alterations of global transcriptional activity. Previously, we had conducted a similar analysis of primary rectal carcinomas. The systematic comparison of colon and rectal carcinomas revealed a significant overlap of genomic imbalances and transcriptional deregulation, including activation of the Wnt/b-catenin signaling cascade, suggesting similar pathogenic pathways. 1) Nuclear topography of aneuploid chromosomes and their consequences on transcriptional activity The 3D-position of chromosome territories in interphase nuclei is non-random and is conserved in evolution. Gene rich chromosomes, such as human chromosome 19, are located towards the center of the nucleus, whereas gene poor chromosomes, such as chromosome 18, are predominantly peripheral in many different cell types. We were eager to explore to which extent this remarkable conservation is maintained in cells containing chromosomal aneuploidies, in particular because we have previously established that these chromosomes are transcriptionally active. Therefore, a relationship could exist between nuclear position and transcriptional activity. We investigated, first, whether aneuploid chromosomes assume a nuclear position similar to that of their endogenous homologues. Using 3D-FISH and confocal laser scanning microscopy, we showed that human chromosomes 7, 18, or 19 introduced via microcell mediated chromosome transfer (MMCT) into the parental diploid colon cancer cell line DLD-1 maintain their conserved position. Our data is thus consistent with the model that each chromosome has an associated zip code that determines its nuclear localization. Whether the nuclear localization determines, or is determined by, the transcriptional activity of resident genes has yet to be ascertained. 2) Aneuploidy, oncogene amplification, and epithelial/mesenchymal transition govern transformation of murine epithelial cells: models for human cancer. We extended these analyses and designed a novel mouse model for colon cancer. Normal primary murine epithelial colon cells were selectively isolated from the large intestine of eight different isogenic C57BL/6 mice. A portion of the primary colon cells were grown in culture under reduced serum conditions while another fraction of these normal cells were cryopreserved for further analysis. The cells were sequentially recovered from culture based on distinct morphological changes: first, cells were in the pre-immortal stage and were actively growing; second, the cells bypassed crisis, formed colonies and became immortal; third, the cells formed foci, became less adherent, and exhibited became tumorigenic when injected into immune-compromised mice. The cells were analyzed at each stage using molecular cytogenetic methods and gene expression profiling. SKY identified recurrent structural and numerical aberrations. Array CGH revealed regions of gene amplifications and deletions. Global gene expression profiling identified deregulated genes specific to each stage of transformation. Three of the late transformed mouse colon cell lines produced tumors in nude mouse assays. This is a unique murine model that reproduces a continued progression of alterations which is common in human colon tumorigenesis. The similarity of the cytogenetic and genetic aberration profiles suggest that this model can serve as a preclinical system for the validation of therapeutic targets. As in human tumors, chromosomal aneuploidies resulted in the transcriptional deregulation of resident genes; in other words, genomic copy number is positively and linearly correlated with transcription levels.